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com
284
Dietary creatine supplementation does not aVect
some haematological indices, or indices of muscle
damage and hepatic and renal function
Tristan M Robinson, Dean A Sewell, Anna Casey, Gery Steenge, Paul L GreenhaV
Abstract
BackgroundThe use of creatine (Cr) as
a nutritional supplement to aid athletic
performance has gained widespread
popularity among athletes. However, con-
cerns have recently been expressed over
potentially harmful eVects of short and
long term Cr supplementation on health.
MethodsForty eight young healthy sub-
jects were randomly allocated to three
experimental protocols aimed at elucidat-
ing any potential health risks associated
with five days (20 g/day) to nine weeks (3
g/day) of Cr supplementation. Venous
blood samples were collected before and
after periods of Cr supplementation and
were analysed for some haematological
indices, and for indices of hepatic, muscu-
lar, and renal dysfunction.
FindingsAll measured indices were well
within their respective normal range at all
times. Serum creatinine concentration
tended to be increased the day after Cr
supplementation. However, values had
returned to baseline six weeks after the
cessation of supplementation. These in-
creases were probably attributable to
increased creatinine production rather
than renal dysfunction. No indication of
impairment to the haematological indices
measured, hepatic function, or muscle
damage was apparent after Cr supple-
mentation.
InterpretationThese data provide evi-
dence that there are no obvious adverse
eVects of acute or more chronic Cr
supplementation on the haematological
indices measured, nor on hepatic, muscle,
and renal function. Therefore there is no
apparent health risk associated with Cr
supplementation to healthy people when it
is ingested in quantities that have been
scientifically proven to increase muscle Cr
School of Biomedical stores.
(Br J Sports Med 2000;34:284288)
Sciences, University of
Nottingham Medical
School, Queens Keywords: creatine supplementation; kidney; liver;
Medical Centre, blood; muscle; exercise; metabolism
Nottingham NG7 2UH,
United Kingdom
T M Robinson Creatine (Cr) metabolism is of interest because
D A Sewell of its pivotal role in energy transduction in cells
A Casey
G Steenge with fluctuating energy demands. Current
P L GreenhaV interests in Cr as a nutritional supplement
include its use as an ergogenic aid1 and its
Correspondence to: potential therapeutic role in conditions such as
Dr P GreenhaV
email: paul.greenhaV@
cardiac insuYciency.2 In recent years Cr
nottingham.ac.uk supplementation has been shown by several
www.bjsportmed.com
Br J Sports Med 2000;34:284288
laboratories to have a positive eVect on the per-
formance of repeated bouts of short lasting
maximal exercise,1 35 the magnitude of which
has been associated with the extent of muscle
Cr accumulation.5 As a result, Cr has become a
very popular dietary supplement used by ama-
teur and professional athletes, with sales in the
United States totalling $100m (60m) during
1997.6
In most studies, a dosing regimen of 20 g Cr
a day for five days7 8 has been used to load
muscles with Cr. The single 5 g dose used in
this regimen can increase plasma Cr concen-
tration by up to 13-fold, which then remains
significantly higher than basal concentration
for three hours.9 It is believed that this
promotes the transport of Cr into muscle and,
after five days of supplementation, results in
about a 25 mmol/kg dry mass increase in mus-
cle total Cr (TCr). The muscle TCr concentra-
tions achieved by this regimen can be main-
tained by continuing Cr ingestion at a
maintenance dose of about 2 g every day,8
which represents the average rate of daily Cr
degradation to creatinine.10
Anecdotal opinions have been expressed6 11
about the potential eVect of ingested Cr on
aspects of health, such as muscle cramping,
muscle-tendon injury, and renal dysfunction.
Opinions such as these, however, have not been
supported with scientific evidence, other than
two recent case reports of renal dysfunction
accompanying oral creatine
supplementation,12 13 one of which was in a
patient with pre-existing kidney disease.12
Despite its apparent widespread use by
athletes,14 there is little published evidence of
the eVects of Cr supplementation on health
indices, such as haematological, hepatic, and
renal function, or muscle damage. The aim of
this study therefore was to obtain information
on such indices in young healthy adult subjects,
before and after a typical regimen of Cr load-
ing, and also after a typical Cr loading and
eight week maintenance regimen.8
Methods
SUBJECTS
Forty eight healthy subjects volunteered to take
part in the series of experiments. None
reported any history of kidney or liver related
illness. All subjects regularly undertook some
form of exercise but none was highly trained.
Before inclusion, informed written consent was
obtained from all of them, and ethical approval
was obtained from the Nottingham University
Medical School ethics committee.
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Creatine and clinical chemistry 285

Table 1 Summary of experimental groups and protocol

Experimental group No and sex Summary of treatment Time of sampling after supplementation

CrLOAD 7, men 5 g Cr + 500 ml CHO drink, 4 times daily, 5 days 1 day

PLOAD 7, men 500 ml CHO drink, 4 times daily, 5 days 1 day
CrLOAD+6 6, men 5 g Cr + 1 g glucose, 4 times daily, 5 days 6 weeks
PLOAD+6 6, 3 men, 3 women 6 g glucose, 4 times daily, 5 days 6 weeks
CrMAINT 7, women 5 g Cr, 4 times daily, 5 days followed by 3 g Cr daily, 8 weeks 1 day
CrMAINT+EX 9, women 5 g Cr, 4 times daily, 5 days followed by 3 g Cr daily, 8 weeks + 1 day
resistance exercise training
PMAINT+EX 6, women 5 g glucose, 4 times daily, 5 days followed by 3 g glucose daily, 8 1 day
weeks + resistance exercise training

CHO, carbohydrate.

EXPERIMENTAL GROUPS and on the day after the maintenance regimen

The 48 subjects were divided randomly into had been completed.
seven experimental groups to examine two dif- Group CrMAINT+EX consisted of nine women
ferent aspects of Cr supplementation (table 1). (age 27 (6) years; BMI 23.4 (3.2) kg/m2) who
ingested a loading dose of 5 g Cr dissolved in a
warm drink four times a day for five days, and
EVects of a Cr loading regimen
who then maintained an intake of 3 g Cr in a
Group CrLOAD consisted of seven men (mean
warm drink, once a day for eight weeks. During
(SD) age 23 (4) years and body mass index
the eight week maintenance period, subjects
(BMI) 22.4 (2.1) kg/m2) who ingested 5 g Cr
engaged in a resistance training programme.
dissolved in a warm drink followed by 500 ml
This exercise programme was used to create
of a carbohydrate-containing solution four
similar conditions to those of subjects who
times a day for five days. This regimen was used
ingest Cr during periods of training to improve
because we have previously shown it to
athletic performance, as anecdotal reports have
augment muscle Cr accumulation by about
been made of muscle cramps occurring during
60% more during five days of Cr loading than
Cr supplementation and training.11 The train-
when Cr alone was ingested.15 This increase in
ing programme involved three one hour super-
Cr accumulation has been attributed to insulin
vised resistance training sessions each week.
augmenting sodium dependent muscle Cr
Blood samples for analysis were obtained as for
transport.15 Blood samples for analysis were
the CrMAINT group.
obtained the day before supplement ingestion
Group PMAINT+EX (a placebo group) consisted
began and the day after the ingestion regimen
of six women (age 28 (5) years; BMI 24.5 (3.6)
had been completed.
kg/m2) who ingested a loading dose of 5 g of
Group PLOAD (a placebo group) consisted of
a glucose polymer dissolved in a warm drink
seven men (age 24 (5) years; BMI 21.3 (0.9)
four times a day for five days, and who then
kg/m2) who ingested 500 ml of a carbohydrate-
maintained an intake of 3 g of glucose polymer
containing solution four times a day for five
in a warm drink, once a day for eight weeks.
days. Blood samples for analysis were obtained
During the eight week supplementation period
as for the CrLOAD group.
subjects engaged in a resistance training
Group CrLOAD+6 consisted of six men (age 24
programme identical with that used by subjects
(3) years; BMI 25.6 (6.3) kg/m2) who ingested
in the CrMAINT+EX group. Blood samples for
5 g Cr plus 1 g glucose dissolved in a warm
analysis were obtained as for the CrMAINT group.
drink four times a day for five days. Blood sam-
ples for analysis were obtained before the start
Supplement formulations
of supplementation and six weeks after the
Subjects in the CrLOAD+6, PLOAD+6, CrMAINT,
ingestion regimen had been completed, when
CrMAINT+EX, and PMAINT+EX groups were provided
muscle Cr stores would be expected to have
with supplements in a double blind manner.
returned to levels found before
During the five day loading dose period,
supplementation.8
subjects in all groups were asked to ingest their
Group PLOAD+6 (a placebo group) consisted of
supplement dose at four regularly spaced inter-
six subjects (age 22 (2) years; BMI 21.7 (2.0)
vals evenly distributed throughout each day.
kg/m2; three men), who ingested 6 g glucose
During the eight week maintenance dose,
dissolved in a warm drink four times a day for
subjects ingested their daily supplement dose
five days. Blood samples for analysis were
at the same time each day. All Cr was given in
obtained as for the CrLOAD+6 group.
its monohydrate powder form (Experimental
and Applied Science, Golden, Colorado,
EVects of Cr loading and an eight week USA). The glucose polymer was provided as
maintenance regimen dextrose powder, and the carbohydrate drink
Group CrMAINT consisted of seven women (age as a commercially available solution (Lucoz-
26 (8) years; BMI 23.3 (1.9) kg/m2) who ade; about 18.5% (w/v) glucose and simple
ingested a loading dose of 5 g Cr dissolved in a sugars; SmithKline Beecham, Coleford,
warm drink four times a day for five days, and Gloucestershire, UK).
who then maintained an intake of 3 g Cr in a
warm drink, once a day for eight weeks. During SAMPLING PROTOCOL
this period, all subjects refrained from per- Subjects reported to the laboratory on the
forming strenuous exercise. Blood samples for morning of the experiments after an overnight
analysis were obtained before supplement fast, having abstained from alcohol consump-
ingestion on the first day of the loading dose tion and strenuous exercise during the previous

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286 Robinson, Sewell, Casey, et al

Table 2 Normal range16 and mean (SD) values of haematological indices and indices of muscle damage and hepatic and renal function before (all
groups), immediately after (CrLOAD, PLOAD groups), and six weeks after (CrLOAD+6, PLOAD+6 groups) five days of creatine (Cr) or placebo (P) ingestion

CrLOAD group PLOAD group CrLOAD+6 group PLOAD+6 group

Clinical index Normal range Pre Post Pre Post Pre 6 weeks Pre 6 weeks

Sodium 135145 141 (2) 141 (1) 141 (2) 142 (1) 139 (1) 141 (1)* 138 (1) 140 (2)
Potassium 3.55.0 4.0 (0.4) 3.9 (0.3) 4.0 (0.3) 4.3 (0.4) 4.0 (0.2) 4.0 (0.3) 4.1 (0.2) 4.0 (0.2)
Urea 2.57.0 4.4 (1.1) 3.8 (1.3) 4.9 (1.0) 3.5 (1.1) 4.1 (0.4) 5.3 (0.6) 4.7 (0.7) 4.2 (0.7)
Creatinine 60130 88 (15) 112 (30) 96 (14) 92 (18) 103 (10) 105 (10) 82 (8) 85 (12)
GGT 065 20 (5) 19 (4) 24 (7) 23 (8) 27 (7) 27 (9) 21 (7) 22 (6)
AP 30110 67 (17) 72 (17) 71 (16) 72 (18) 72 (9) 72 (13) 64 (15) 61 (15)
ALT 540 25 (7) 24 (7) 22 (3) 25 (4) 27 (8) 30 (7) 19 (3) 21 (3)
Albumin 3550 44 (3) 43 (2) 44 (2) 44 (2) 47 (4) 45 (1) 47 (2) 45 (2)
Bilirubin 517 14 (5) 12 (6) 16 (3) 12 (3) 12 (2) 10 (2) 12 (4) 10 (3)
CK Up to 200 Not measured Not measured 152 (85) 127 (34) 92 (42) 123 (108)
Hb 11.518.0 14.0 (0.8) 14.0 (0.9) 14.6 (0.3) 14.4 (0.6) 14.9 (0.8) 14.7 (0.6) 13.9 (1.3) 13.4 (1.1)
WBC 4.011.0 5.0 (1.5) 5.5 (0.9) 5.7 (1.4) 7.0 (1.4) 6.2 (1.0) 6.7 (1.3) 5.3 (1.4) 5.3 (1.2)
Platelets 150400 197 (47) 212 (39) 233 (63) 243 (60) 263 (48) 236 (40) 223 (62) 214 (43)

Measurement units for haematological indices and indices of muscle damage and hepatic and renal function; sodium (mmol/l), potassium (mmol/l), urea (mmol/l),
creatinine (mol/l), -glutamyl transferase (GGT; U/l), alkaline phosphatase (AP; U/l), alanine aminotransferase (ALT; U/l), albumin (g/l), total bilirubin (mol/l),
creatine kinase (CK; U/l), haemoglobin (Hb; g/100 ml), white blood cells (WBC; 109/l), platelets (109/l).
*p<0.05, p<0.01, and p<0.001 indicate significant diVerences between the values before (Pre) and after (Post) supplementation within each group.

48 hours. Height and body mass (in under- STATISTICAL ANALYSIS

wear) were recorded. Blood samples were
taken at rest by venepuncture (using the Vacu-
tainer system, from an antecubital vein of the
left or right arm) after subjects had been seated
for at least five minutes. Samples for clinical
chemistry analyses were dispensed into plain
tubes (containing no anticoagulant), and sam-
ples for haematological analysis were dispensed
into tubes containing EDTA. Samples were
subsequently analysed for indices of renal
function (serum sodium, potassium, urea, and
creatinine concentrations), hepatic function
(serum -glutamyl transferase, alkaline phos-
phatase, and alanine aminotransferase activity,
and albumin and total bilirubin concentra-
tions), and indices of haematological function
(haemoglobin concentration was measured
and white blood cells and platelets counted). In
addition, an index of muscle damage (serum
creatine kinase activity) was measured in the
groups assessed six weeks after acute supple-
mentation and after the more chronic mainte-
nance regimen. All analyses were by routine
methods in use at the University Hospital,
Queens Medical Centre, Nottingham.
Students t test was used to compare values
determined before and after supplementation
in each of the groups (paired), and to compare
the changes between corresponding Cr and
placebo groups (unpaired), using a commer-
cially available computer software package
(Microsoft Excel). Statistical significance was
declared at p<0.05.
Results
All subjects reported adherence to the experi-
mental protocol and complete ingestion of the
supplements. None reported any adverse
eVects throughout the period of the study.
EFFECTS OF A Cr LOADING DOSE REGIMEN
Group mean data of all indices measured were
within the normal range before, the day after,
and six weeks after the loading regimen (table
2). On the day after Cr loading, there was no
significant diVerence in any of the indices
measured before Cr loading; however, moder-
ate decreases were observed in serum urea and
bilirubin concentrations of the placebo group.
Although there were no diVerences in absolute
concentrations, there was a significant between

Table 3 Normal range16 and mean (SD) values of haematological indices and indices of muscle damage and hepatic and
renal function before and immediately after five days of creatine or placebo ingestion followed by an eight week Cr or
placebo maintenance regimen in the presence and absence of exercise training

CrMAINT+EX group CrMAINT group PMAINT+EX group

Clinical index Normal range Pre Post Pre Post Pre Post

Sodium 135145 140 (2) 139 (2) 140 (2) 140 (1) 141 (2) 140 (1)
Potassium 3.55.0 3.9 (0.2) 4.1 (0.2) 3.9 (0.2) 4.1 (0.3) 3.9 (0.3) 4.2 (0.2)
Urea 2.57.0 3.6 (0.7) 3.6 (0.8) 4.2 (0.7) 3.8 (0.4) 4.3 (0.6) 3.6 (0.8)
Creatinine 54117 69 (6) 86 (15)* 68 (4) 95 (17)* 78 (9) 72 (5)
GGT 040 19 (5) 21 (4) 19 (5) 20 (4) 41 (54) 31 (28)
AP 30110 52 (6) 60 (12) 53 (8) 55 (9) 67 (18) 64 (11)
ALT 540 27 (4) 22 (3) 26 (4) 21 (4) 30 (5) 28 (9)
Albumin 3550 40 (2) 43 (2) 40 (3) 44 (3) 41 (3) 43 (2)
Bilirubin 517 10 (4) 10 (2) 9 (2) 10 (2) 12 (6) 12 (2)
CK up to 200 142 (149) 142 (48) 91 (59) 91 (34) 186 (194) 198 (145)
Hb 11.516.5 12.2 (1.0) 12.2 (0.8) 12.3 (1.1) 12.8 (0.8) 13.3 (1.0) 13.2 (1.1)
WBC 4.011.0 5.9 (0.6) 6.2 (1.2) 6.5 (1.3) 6.8 (1.5) 6.7 (1.4) 6.0 (0.6)
Platelets 150400 244 (59) 249 (58) 268 (21) 292 (59) 274 (43) 267 (70)

Measurement units for haematological indices and indices of muscle damage and hepatic and renal function; sodium (mmol/l),
potassium (mmol/l), urea (mmol/l), creatinine (mol/l), -glutamyl transferase (GGT; U/l), alkaline phosphatase (AP; U/l), alanine
aminotransferase (ALT; U/l), albumin (g/l), total bilirubin (mol/l), creatine kinase (CK; U/l), haemoglobin (Hb; g/100 ml), white
blood cells (WBC; 109/l), platelets (109/l).
*p<0.05 and p<0.01 indicate significant diVerences between values before (Pre) and after (Post) supplementation within each
group.

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Creatine and clinical chemistry
group diVerence in the change in serum creati-
nine concentration over time (CrLOAD, 24 (10)
mol/l; PLOAD, 3 (2) mol/l; p<0.05). This dif-
ference was not evident six weeks after the
completion of the loading dose (CrLOAD+6, 2 (2)
mol/l; PLOAD+6, 3 (2) mol/l; p>0.05). Serum
sodium and urea concentrations had increased
in the CrLOAD+6 group six weeks after completion
of Cr loading (table 2). The change in serum
urea concentration with time was significantly
diVerent in the CrLOAD+6 group compared with
its placebo group (CrLOAD+6, 1.2 (0.3) mmol/l;
PLOAD+6, 0.4 (0.2) mmol/l; p<0.001). A
moderate decrease in serum albumin concen-
tration was observed in the PLOAD+6 group.
EFFECTS OF A Cr MAINTENANCE DOSE REGIMEN
Group mean data of all indices measured were
within the normal range before the Cr loading
regimen and on the day after the maintenance
regimen was completed (table 3). Small to
moderate increases in serum potassium, creati-
nine, and albumin were observed in both
groups receiving Cr. In addition, there was a
small decrease in alanine aminotransferase
concentration in the CrMAINT group and an
increase in alkaline phosphatase in the
CrMAINT+EX group. There was a significant
decrease in serum urea concentration in the
PMAINT+EX group. The changes in serum creati-
nine concentration over time in the groups
receiving Cr were significantly diVerent from
those in the placebo group (CrMAINT, 26 (6)
mol/l; CrMAINT+EX, 17 (4) mol/l; PMAINT+EX, 6
(3) mol/l; p<0.001, p<0.01 respectively).
Discussion
We believe that this is the first detailed
information to be reported on the eVects of
short term (20 g/day for five days) and more
chronic (3 g/day for 56 days) Cr supplementa-
tion on a range of some haematological indices
and indices of hepatic, muscle, and renal func-
tion, in young healthy adults. Information on
some of these indices in older adults (older
than 51) during eight weeks of Cr supplemen-
tation has been published in abstract form,17 18
while more recent work has reported some
clinical chemistry indices in male athletes
ingesting Cr for 28 days,19 and renal responses
in healthy men after short term
supplementation.20 In none of these reports
were adverse responses reported. Data from
blood samples taken before supplementation,
on the day after, and six weeks after an
established Cr loading dose regimen, and after
a subsequent eight week maintenance dose of 3
g/day have been examined in this study. Mean
concentrations of all indices were well within
the normal range16 at all times.
Creatinine has been established as the sole
end product of Cr degradation, being formed
non-enzymatically in an irreversible
reaction.21 22 As skeletal muscle is the major
store of the body Cr pool,10 it is therefore the
main site of creatinine production. In normal
healthy people, plasma creatinine concentra-
tion is dependent on total muscle mass,23 thus
daily renal creatinine excretion is relatively
constant in a given individual, but can vary
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287
between individuals.24 In the present study,
serum creatinine concentration on the day after
Cr loading was within the normal range and
was not significantly higher than that before
supplementation. However, the relative change
in concentration over time was significantly
greater in the CrLOAD group than in the placebo
group. This diVerence in the change in serum
creatinine concentration merely reflects an
increased rate of muscle creatinine formation
as a result of the dietary induced increase in
muscle Cr stores, and has been reported previ-
ously, together with a parallel increase in
urinary creatinine excretion.8 Six weeks after
discontinuation of Cr loading, there was no
indication of an elevated serum creatinine con-
centration. Muscle TCr will have returned
close to the level found before supplementation
by this time,8 as will have renal creatinine
excretion. Maintaining elevated muscle Cr
concentration by ingesting 3 g Cr a day after Cr
loading increased serum creatinine concentra-
tion above that seen before supplementation.
However, these concentrations were again
within the normal range and, as outlined
above, were probably attributable to the
increase in muscle Cr concentration.
We suggest that the increase in serum urea
six weeks after the Cr loading regimen is of lit-
tle clinical significance and unlikely to be a
direct result of Cr supplementation. This con-
tention is supported by the lack of any
diVerence in serum urea concentration on the
day after a Cr loading regimen and after more
chronic supplementation with and without
training.
Serum sodium concentration was increased
six weeks after Cr loading. However, the
absence of any similar change on the day after
the end of supplementation suggests that this
was unlikely to be due to supplementation, and
the magnitude of the change would be
expected to be of little clinical significance.
Similarly, the increase in serum potassium
concentration after chronic Cr supplementa-
tion was small and unlikely to be of clinical sig-
nificance.
All hepatic function indices were within the
normal limits before and after creatine loading.
The changes observed in serum alkaline phos-
phatase (CrMAINT+EX) and alanine aminotrans-
ferase (CrMAINT) activity and albumin (PLOAD+6,
CrMAINT+EX, CrMAINT) and bilirubin (PLOAD) con-
centrations with time were all marginal and
occurred in both directions. We suggest that
these changes are unlikely to be of clinical sig-
nificance and probably unrelated to the experi-
mental protocol.
The haematological indices measured were
unchanged by the supplementation protocols.
Serum creatine kinase activity, an accepted
marker of muscle damage, was unchanged six
weeks after acute Cr supplementation, nor was
it changed after more chronic supplementation
in the presence and absence of resistance train-
ing. This latter finding is of interest, as anecdo-
tal comments have linked Cr supplementation
to the development of muscle cramps and
muscle-tendon injury during or after exercise.11
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288 Robinson, Sewell, Casey, et al

In the present study, there were no reports of
muscle cramping or injury.
In conclusion, no clinically significant
changes in the haematological indices
measured, nor in indices of muscle damage or
hepatic and renal function, were observed after
acute Cr loading or eight weeks of lower dose
maintenance ingestion. The present data there-
fore suggest that there is no obvious risk to
health of ingesting creatine supplements. In-
deed, the 23 g a day maintenance dose of Cr
currently advocated to maintain muscle Cr
concentration after Cr loading8 is similar to the
amount of Cr used daily by the body and could
be partly achieved from meat and fish inges-
tion.
The authors wish to thank Ms Elizabeth Simpson of the School
of Biomedical Sciences and the staV of the Departments of
Clinical Chemistry and Haematology at the University
Hospital, Queens Medical Centre, Nottingham for their
technical support. This research was supported by the Defence
Research Agency and Experimental and Applied Sciences.
Contributors: All authors participated in the design and
execution of the study protocol, discussed the interpretation of
the findings, and contributed to the paper. T R participated in
data collection, statistical analysis, and writing of the paper. D S
participated in data collection, statistical analysis, and writing of
the paper. A C participated in data collection and edited the
paper. G S participated in data collection and edited the paper.
P G initiated the research and edited the paper. P G will act as
guarantor.
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Take home message

Recently there have been some concerns that creatine supplementation may have adverse
eVects on health. This paper investigated the eVect of acute and more prolonged creatine sup-
plementation on some haematological indices and indices of hepatic, muscle, and renal func-
tion. The data presented provide evidence that there are no adverse eVects of acute or more
chronic creatine supplementation on any of the indices measured and suggest that that there is
no obvious risk to health of ingesting creatine supplements at the recommended doses.

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Dietary creatine supplementation does not

affect some haematological indices, or indices
of muscle damage and hepatic and renal
function
Tristan M Robinson, Dean A Sewell, Anna Casey, et al.

Br J Sports Med 2000 34: 284-288

doi: 10.1136/bjsm.34.4.284

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